Thermographic imaging

ABSTRACT

There is provided a method of and apparatus for thermographic imaging involving the use in electron spin resonance enhanced magnetic resonance imaging (ESREMRI) of a paramagnetic contrast agent having in its esr spectrum a temperature dependant transition. The ESREMRI enhancement of the free induction decay signal resultant on stimulating that transition with radiation of a set frequency or frequency band is itself accordingly temperature dependant.

BACKGROUND OF THE INVENTION

The present invention relates to improvements in and relating tomagnetic resonance imaging (MRI) apparatus and methods, and inparticular to a method and apparatus for the thermographic imaging of asubject, generally although not essentially a human or animal body, andto contrast agents and media for use in such methods.

In certain cancer treatments, malignant tissue within the body isdestroyed by irradiation with radiation, for example microwaveradiation, which has sufficient heating effect to kill the malignanttissue, e.g. by raising the local temperature to about 43° C. As willreadily be appreciated, the heating radiation can also kill healthytissue and it is therefore of great importance for such treatments forthe physician to be able to determine the temperature at and near theirradiated site.

This is particularly important since the radiation reflection andabsorption characteristics are not uniform throughout the body and,especially where two or more directed radiation sources are used toachieve the heating effect, there is a danger that radiation reflectionor shadowing by body tissue may cause areas of significant temperatureincrease ("hot-spots") to occur in healthy tissue or may prevent thetemperature increase in part or all of the malignant tissue site frombeing sufficient to kill off all the malignant cells.

Several methods of temperature monitoring have been proposed, but todate all such methods have been either invasive, insufficiently accurateor time consuming or have enabled temperatures to be measured forsuperficial tissue layers only. Thus typical techniques which have beenused include invasive monitoring by insertion of thermal sensing probes,infrared thermography, CAT scanning and NMR relaxation rate assessments.

There remains a need for a non-invasive thermographic imaging methodcapable of determining local temperatures throughout the body withreasonable accuracy.

We have now found that using a modification of our recently developedElectron Spin Resonance Enhanced Magnetic Resonance Imaging (ESREMRI)method thermographic imaging, or temperature monitoring, can beeffected.

MRI is a diagnostic technique that has become particularly attractive tophysicians as it does not involve exposing the patient to the harmfulX-or gamma-radiations of conventional radiographic imaging techniques.

In our co-pending European Patent Application EP-A-296833 and BritishPatent Applications Nos. 8817137 and 8819753.8 we have described how theintensity of the magnetic resonance (MR) signal from which MR images arebuilt up may be enhanced, e.g. by factors of 100 or more, by exciting anesr transition of a paramagnetic substance present within the subjectbeing imaged where that esr transition is coupled to the nmr transitionof the nuclei (generally protons and usually protons in water molecules)which emit the MR signals from which the MR images are built up.

The degeneracy of the spin states of nuclei with non-zero spin, e.g. ¹H, ¹³ C, ¹⁹ F, etc., is lost when such nuclei are within a magneticfield and transitions between the ground and excited spin states can beexcited by the application of radiation of the frequency (ω_(o))corresponding to energy difference E of the transition (i.e. ω_(o) = E).This frequency is termed the Larmor frequency and is proportional to thestrength of the applied field. As there is an energy difference betweenthe spin states, when the spin system is at equilibrium the populationdistribution between ground and excited spin states is a Boltzmanndistribution and there is a relative overpopulation of the ground stateresulting in the spin system as a whole possessing a net magnetic momentin the field direction. This is referred to as a longitudinalmagnetization. At equilibrium the components of the magnetic moments ofthe individual non-zero spin nuclei in the plane perpendicular to thefield direction are randomized and the spin system as a whole has no netmagnetic moment in this plane, i.e. it has no tranverse magnetization.

If the spin system is then exposed to a relatively low intensityoscillating magnetic field perpendicular to the main field and producedby radiation at the Larmor frequency, generally radiofrequency (RF)radiation in conventional MRI, transitions between ground and excitedspin states occur. If the exposure is for a relatively short durationthen the resultant magnitudes of the longitudinal and transversemagnetizations of the spin system are functions of the exposure durationwhich oscillate about zero at the Larmor frequency and are 90° out ofphase with each other. Thus, from equilibrium, a pulse of duration(2n+1)π/2ω_(o) (a so-called 90° pulse when n is even and a 270° pulsewhen n is odd) leaves the system with maximum transverse magnetization(of magnitude proportional to the initial longitudinal magnetization atequilibrium) and no longitudinal magnetization, a pulse of duration(2n+1)π/ω_(o) (a 180° pulse) leaves the system with invertedlongitudinal magnetization and inverted transverse magnetization (andhence from equilibrium no transverse magnetization), etc.

When the pulse is terminated, the oscillating magnetic field produced byany resulting net transverse magnetization can induce an oscillatingelectrical signal (of angular frequency ω_(o)) in a detector coil havingits axis arranged perpendicular to the main field direction. For thispurpose the transmitter used to emit the pulse can also be used as adetector.

Induced nuclear magnetic resonance signals, hereinafter termed freeinduction decay (FID) signals, have an amplitude proportional to thetransverse magnetization (and hence generally to the original populationdifference between ground and excited spin states).

If the nuclei of the spin system experienced an entirely uniformmagnetic field, the FID signal would decay due to spin-spin interactionsat a rate with a characteristic time of T₂, the transverse or spin-spinrelaxation time. However, due to local field inhomogeneities, the nucleiwithin the spin system will have a spread of Larmor frequencies anddecay of transverse magnetization is more rapid, having a characteristictime of T₂ * where 1/T₂ * =1/T₂ +1/T_(inh), T_(inh) representing thecontribution due to field inhomogeneities. T₂ itself can be determinedusing spin-echo imaging in which, after the decay of the FID signal(usually following a 90° pulse) the system is exposed to a 180° pulseand an "echo" signal is generated, the decay in the amplitude of theecho being governed primarily by T₂ as, with the inversion of thetransverse magnetization for the individual nuclei, the fieldinhomogeneities referred to above cause tranverse magnetization to buildup to a maximum at time TE/2 after the 180° pulse where the time betweenthe previous maximum transverse magnetization and the 180° pulse is alsoTE/2.

To generate different images, different pulse and FID detectionsequences are used. Perhaps the simplest is saturation recovery (SR)where the FID signal is determined after a single 90° initiating pulse.The signal strength is dependent upon the magnitude of the longitudinalmagnetization before the pulse, and hence on the nuclear density and theextent to which the system reequilibrates in the time (TR) betweensuccessive initiating pulses. In spin-echo imaging, for examplemultiple-echo imaging, the pulse and detection sequence may be:initiating 90° pulse (at time 0), FID detection (following theinitiating pulse), 180° pulse (at time TE/2), detection of 1st echo (attime TE), 180° pulse (at time 3TE/2), detection of 2nd echo (at time2TE) . . . , initiating pulse for the next sequence (at time TR), etc.In this technique, a TR is selected which is sufficient for a reasonablereequilibration to occur in the period between successive initiatingpulses.

As is explained further below in connection with the example of twodimensional Fourier transformation (2DFT) image generation, in order togenerate a single image with adequate spatial resolution, it isnecessary to perform a large number (e.g. 64-1024) of separate pulse anddetection sequences.

Since TR has in principle to be large with respect to T₁, thecharacteristic time for relaxation of the excited system towards theequilibrium Boltzmann distribution between ground and excited spinstates, to permit longitudinal magnetization to build up betweensuccessive pulse sequences so as to avoid the FID signal strengthdecaying in successive pulse sequences, the total image acquistion timeis generally relatively large. Thus, for example, TR may conventionallybe of the order of seconds and the image acquisition time may be of theorder of 10-30 minutes.

Certain so-called fast imaging (FI) techniques may be used to acceleratereequilibration and so reduce image acquisition time; however theyinherently result in a reduction in the S/N ratio and/or contrast hencein poorer image quality. The FI technique involves for example excitingthe spin system with a less than 90° pulse and thus the differencebetween ground and excited spin state populations is only reduced ratherthan eliminated (as with a 90° pulse) or inverted and so reattainment ofequilibrium is more rapid. Nevertheless, the transverse magnetizationgenerated by the less than 90° pulse is less than that for a 90° pulseand so FID signal strength and thus S/N ratio and the spatial resolutionin the final image are reduced.

Using different pulse and detection sequences and by manipulation of theacquired data, MRI can be used to generate a variety of differentimages, for example saturation recovery (SR), inversion recovery (IR),spin echo (SE), nuclear (usually proton) density, longitudinalrelaxation time (T₁) and transverse relaxation time (T₂) images. Tissuesor tissue abnormalities that have poor contrast in one such image oftenhave improved contrast in another. Alternatively, imaging parameters(nuclear density, T₁ and T₂) for tissues of interest may be altered byadministration of a contrast agent. Thus many proposals have been madefor the administration of magnetically responsive materials to patientsunder study (see for example EP-A-71564 (Schering), U.S. Pat. No.4,615,879 (Runge), WO-A-85/02772 (Schroder) and WO-A-85/04330(Jacobsen)). Where such materials, generally referred to as MRI contrastagents, are paramagnetic (for example gadolinium oxalate as suggested byRunge) they produce a significant reduction in the T₁ of the waterprotons in the zones into which they are administered or at which theycongregate, and where the materials are ferromagnetic orsuperparamagnetic (e.g. as suggested by Schroder and Jacobsen) theyproduce a significant reduction in the T₂ of the water protons, ineither case resulting in enhanced (positive or negative) contrast in themagnetic resonance (MR) images of such zones.

The contrast enhancement achievable by such agents is limited by anumber of factors. Thus such contrast agents cannot move the MRI signalintensity (I_(s)) for any tissue beyond the maximum (I_(l)) and minimum(I_(o)) intensities achievable for that tissue using the same imagingtechnique (e.g. IR, SR, SE, etc.) in the absence of the contrast agent:thus if "contrast effect" is defined as (I_(s) -I_(o))/(I_(l) -I_(o)),contrast agents can serve to alter the "contrast effect" of a tissuewithin the range of 0-1. However to achieve contrast improvement anadequate quantity of the contrast agent must be administered to thesubject, either directly to the body site of interest or in such a waythat the natural operation of the body will bring the contrast agent tothat body site.

ESREMRI utilises the spin transition coupling phenomenon known inconventional nmr spectroscopy as the Overhauser effect to amplify thepopulation difference between ground and excited nuclear spin states,producing a significant overpopulation (relative to the Boltzmanndistribution population) of the excited spin state of the nuclear spinsystem producing the MR image. This is achieved by exciting a coupledesr transition in a paramagnetic species naturally occurring in orintroduced into the sample being imaged, which is generally but notessentially a human or animal subject.

The MRI apparatus for use according to this technique requires a secondradiation source for generating the radiation capable of stimulatingsuch an esr transition as well as the first radiation source forgenerating the radiation used to stimulate the nuclear spin transition.

SUMMARY OF THE INVENTION

The present invention is based on the fact that many paramagneticspecies have esr spectra in which one or more of the peaks istemperature dependent. By carrying out the ESREMRI technique using aconstant MW source at the central frequency of the temperature dependentpeak at a reference temperature, e.g. ambient temperature, the shiftcaused by increased temperature will move the peak relative to the MWfrequency and thus alter the resonance induced; this in turn alters theesr enhancement of the FID signal and the extent of this alteration canbe used to estimate the temperature difference from the referencetemperature.

In general, the esr spectrum will consist of peaks of significant linewidth and will thus lie between limiting frequencies on either side ofthe central frequency. The shape of the peak is thus such that there isa continuous and well defined fall in signal strength on moving awayfrom the central frequency. Provided the frequency shift due to changingtemperature is not so great that MW frequency falls outside the limitingfrequencies of the peak after the temperature change, the signalstrength on stimulation with constant MW frequency as described abovewill alter in a relatively continuous and calculable way as thetemperature changes. If the frequency shift is so large as not to fulfilthis requirement, then it is possible to repeat the ESREMRI measurementusing a constant MW frequency corresponding to a reference temperaturecloser to the temperature to be measured.

Viewed from one aspect the present invention provides a method ofdetermining temperature of at least one site of a body containing aparamagnetic substance having a first esr transition the centralfrequency of which is temperature dependent, said method comprisingexposing said body to a first radiation of a frequency selected toexcite nuclear spin transitions in selected nuclei in said body,exposing said body to a second radiation of a frequency selected toexcite said esr transition, said second radiation being at the centralfrequency of the said esr transition at a selected referencetemperature, detecting free induction decay signals from the body, andfrom the said free induction decay signals generating a signalindicative of the temperature at said site and, optionally, generatingan image indicative of temperature distribution in said body.

DETAILED DESCRIPTION OF THE INVENTION

In the methods of the invention exposure of the body to the RF radiationwill generally be in a series of pulse sequences with exposure to MWradiation occurring during at least one and generally a plurality ofsuch sequences.

It will be appreciated that the reference temperature may be differentfrom ambient temperature, conveniently above ambient where elevatedtemperatures are to be measured. Thus in effect, the MW frequency of thesecond radiation may be any frequency corresponding to a temperatureclose enough to the unknown temperature to ensure that the frequencystill falls within the frequency limits of the temperature-shifted esrpeak at some part of the temperature range of interest.

For temperature measurement at one or more sites within the body beingexamined (voxels) it will be necessary to use the techniques of MRI andfor this there will thus be at least a magnetic field gradient toprovide the necessary slicing and normally phase encoding and readgradients will be applied at the appropriate times. In this way, eitherindividual voxels within the body can be examined or a completetopographic thermal image of the body can be built up.

In general, the free induction decay (FID) signals from any particularvolume (voxel) within the said body will depend on a number ofparameters each of which may vary widely, so that the magnitude of theFID signals alone will in most cases give only an inaccurate estimationof temperature. Consequently, it is in general desirable to employ meanswhereby the effect of the variable paramaters can be eliminated.

One parameter of importance is the concentration of the paramagneticspecies in the voxel concerned. In human tissue, relative uptakes of theparamagnetic species are not at all uniform even in a single tissue.Thus, a low FID signal could be due to low concentration of theparamagnetic species at the voxel concerned and if the concentration isunknown and/or variable, it will be difficult to derive the temperaturechange from the FID information.

The MW power that is the power of the esr exciting radiation, at anyparticular voxel will be generally lower than the applied MW power dueto absorption by intervening tissue and other factors. Again, areduction in local MW power gives a lower FID signal and will berelevant to the temperature determination.

Other variable parameters are T₁ and T₂ of the esr transition (T_(1e)and T_(2e)).

The equations and explanations for signal enhancement variations areoffered by way of illustration and the efficacy and utility of theinvention is in no way dependent on their accuracy. Thus the enhancementcaused by esr transition stimulation and the FID signal strength can forlarge enhancements and short repetition times be represented by Equation1:

    E=1/2K.sub.1 (1-(1+F(P.sub.v.WL.Δt)+WL.Y.sup.2.P.sub.v).sup.-1)(1-e .sup.K 2.sup.c)

where

E represents the signal enhancement;

Δt is the difference between the temperature of the voxel and thereference temperature;

WL is the product of T_(1e) and T_(2e) where T_(1e) is T₁ for the esrtransition and T_(2e) is T₂ for the esr transition;

K₁ is the gyromagnetic ratio of the electron to the proton

Y is the gyromagnetic constant of the electron;

P_(v) is the MW power within the voxel;

C is the concentration of the paramagnetic substance within the voxel;

K₂ is a constant; and

F(P_(v), WL, Δt) is a function related to the change from saturation ormaximum resonance due to the temperature change, being zero where thereis no temperature dependent change. This function is dependent on Δt inthe sense that the shift in the position of the central frequency of thetemperature dependent esr peak is proportional to Δt.

Since enhancement of the FID signal can be up to 100 or even 200 times,the enhancement will be the predominant factor in determining FID signalstrength and consequently as an approximation, the signal strength S canbe represented as KE where K is a constant. In general, therefore, theeffect of the nature of the RF pulse sequence and of the possible effectof sub-volumes of zero concentration of contrast agent in the volume orvoxel to be investigated can be excluded, particularly when ratios ofFID signal strengths are concerned as in the calculations discussedbelow.

If it were possible to keep all the variable parameters constant, thenmeasurement of the reduced FID signal would be capable of providing thetemperature change directly, either by calculation or calibration. Inpractice, this is extremely difficult, and according to a furtherpreferred aspect of the invention; we reduce this problem by selecting aparamagnetic substance which has at least two esr transitions, one ofwhich is invariant with temperature and one of which is temperaturedependent.

We have found that certain nitroxide free radicals used as paramagneticcontrast agents in ESREMRI, in particular 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl, have an esr spectrum comprising a triplet the centralpeak of which is temperature invariant and the side peaks of which aretemperature dependent.

According to this important embodiment of the invention, in addition tothe radiation exciting the temperature dependent esr transition, andthat exciting nuclear spin transitions, the body is also exposed to athird radiation exciting a second esr transition, the central frequencyof which is substantially temperature independent. Conveniently in thisembodiment the body is exposed to a series of pulse sequences of thefirst radiation and is exposed to the second radiation during a firstset of the sequences and to the third radiation during a second set ofthe sequences. The signal or image indicative of temperature can then begenerated from the FID signals detected in the first and second sets,e.g. pluralities, of pulse sequences.

In this case, the second esr transition will be at resonance throughoutand the function F(P_(v).WL.Δt) in the above equation will be zero.Furthermore many of the parameters in Equation 1, in particular localconcentration of the paramagnetic contrast agent, will be the same inrespect of both transitions and consequently, the ratio of the FIDsignals, being approximately proportional to the respective signalenhancements, will exclude many of the common terms by cancelling out.

Since Y is a constant, under the above circumstances, the only othervariable parameter in Equation (1) is P_(v), the local MW power at thevoxel. If the relative strengths of the FID signals for the twotransitions are determined again at a different applied MW power level,it is possible to eliminate P_(v) on the experimentally verifiedassumption that P_(v) is a constant fraction of the applied power. P_(v)can thus be replaced in the above equation by A.P, where P is theapplied MW power and A is a constant for the voxel concerned related tothe transmission (i.e. non-absorption) of the MW radiation at that site.

It should be noted that since the two esr peaks are part of a multiplet,usually a triplet, the esr relaxation time T_(1e) is the same for bothpeaks, as is T_(2e) and WL will thus be substantially the same for bothpeaks and for any particular voxel will be the same in each of theequations for the FID signal strength as set out below.

One can thus derive equations as follows:

Temperature Invariant Peak A ##EQU1## (where S₁ ^(A) and E₁ ^(A) are theFID signal stengths and enhancement factor E for peak A at power level 1and SR₁,2^(A) ratio of FID signal strengths S₁ ^(A) and S₂ ^(A)) becauseF(AP,Δt,WL) is zero when there is no change from resonance withtemperature (i.e. when Δt is zero), and WL is substantially the same forboth power settings. This enables the product (Y², WL A) to bedetermined knowing P₁ and P₂ and thus the value of A.WL. TemperatureVariable Peak, B ##EQU2##

Since A.WL has been determined and P₁ and P₂ are known, the latterequation can be solved for F(AP,WL,Δt). It will be noted that since theterm (1-e^(K) 2^(c)) in Equation (1) remains the same throughout, itcancels out when ratios of FID signal strengths are determined.

The nature of the function F(AP.WL.Δt), which is related to the shape ofthe esr peak, can be determined by preliminary calculation andcalibration for different levels of power, WL and temperature. From suchcalibration, it is possible to readily derive Δt from the value for F(AP₁.WL,Δt). It should be noted that although WL and A may vary fromvoxel to voxel, partly due to concentration effects, the abovecalculation will be made independently for each voxel and it is onlynecessary that WL and A are the same throughout the equations for theparticular voxel concerned.

However, the sign of the function F(AP,Δt,WL) will be the same for bothupward and downward temperature changes, because the substantiallysymmetrical shape of the esr peak means that departures from resonanceor saturation will be caused by both upward and downward temperaturechanges, it may be necessary to establish whether Δt has a +ve or -vesign. Where it is possible to establish a definite increase intemperature by other means, this may not be necessary but in general, afurther step is required to determine the sign of Δt.

This can, however, readily be achieved by a further determination of theFID signal strength using an MW frequency close to but different fromthe MW frequency providing resonance at the reference temperature, forexample an MW frequency corresponding to resonance at a temperatureslightly above the reference temperature. The method of the inventionwill then involve exposing the body to a fourth radiation of a frequencyselected to excite the first esr transition the fourth radiation beingat the central frequency of said first esr transition at a secondselected reference temperature. If Δt is positive, that is thetemperature has increased, the esr transition will be closer toresonance which will increase the signal enhancement factor E and thusthe FID signal thereby indicating the positive sign of Δt.

In fact, this further measurement can, under some circumstances, takentogether with the FID signal at the original MW frequency for thetemperature dependent peak, provide sufficient information to enable tto be determined without reference to the temperature invariant peak.

Thus, the most preferred procedure according to the invention formeasuring temperature at a site in a body, for example a human body, isas follows:

1. Cause a paramagnetic MRI contrast agent of the appropriate kind to bedistributed throughout the body.

2. Expose the body under magnetic field conditions for generating FIDsignals at that said site to a series of pulse sequences of the firstradiation exciting nuclear spin transition (normally proton spintransitions since, in the case of the human body, water molecules areadequately widely distributed).

3. Expose the body within a first plurality of the pulse sequences of(2) to a second radiation being at the central frequency of atemperature dependent esr transition of the contrast agent, saidfrequency being that causing maximum resonance at a referencetemperature and being at a constant, known power level.

4. Measuring the FID signals so generated.

5. Expose the body within a second plurality of the pulse sequences of(2) under the same magnetic field conditions (and thus relating toessentially the same voxel) at the, central frequency of a temperatureindependent esr transition of the paramagnetic substance and being atthe same power level as (3).

6. Measuring the FID signals from the body generated by (5).

7. Repeating (2) to (6) under the same magnetic field conditions atdifferent power level of the two esr exciting frequencies.

8. Repeating (3) and (4) under the same magnetic field conditions at aslightly different frequency in order to determine the sign of thetemperature deviation from the reference temperature, Δt.

9. By a suitable algorithm, solving the foregoing equations to give avalue of Δt in a particular voxel of the body.

10. If desired, repeating steps (1)-(9) at different magnetic fieldsettings to determine Δt in different voxels of the body, for example,producing a thermal tomographic image of the body.

Thus the method of the invention preferably involves the followingsteps:

a) distributing a said paramagnetic substance within said body;

b) exposing said body to a series of pulse sequences of said firstradiation;

c) exposing said body during a first set of said sequences to saidsecond radiation at a first selected power level;

d) detecting free induction decay signals from said body in said firstset of sequences;

e) exposing said body during a second set of said sequences to saidthird radiation at said first selected power level;

f) detecting free induction decay signals from said body in said secondset of sequences;

g) exposing said body during a third set of said sequences to saidsecond radiation at a second selected power level;

h) detecting free induction decay signals from said body in said thirdset of sequences;

i) exposing said body during a fourth set of said sequences to saidthird radiation at said second selected power level;

j) detecting free induction decay signals from said body in said fourthset of sequences;

k) exposing said body during a fifth set of said sequences to saidfourth radiation at said first selected power level;

l) detecting free induction decay signals from said body in said fifthset of sequences; and

m) generating from the free induction signals detected in steps (d),(f), (h), (j) and (l) a said signal or image indicative of temperature.

It will be appreciated that the applied MW power should be selected toensure that the signal enhancement is adequately temperature dependent.Furthermore, the MW power should not be such that undue heating of thebody takes place. Such heating can be reduced by selecting esrtransitions in which T_(1e) and T_(2e) are both long; the nitroxide freeradical contrast agents are satisfactory in this respect.

For the performance of the method of the invention there may be used anESREMRI apparatus provided with a nuclear magnetic resonance transitionstimulating radiation source and a source or sources for at least one,preferably two or more, esr transition stimulating radiation, andpreferably provided with means for adjusting power levels of at leastthe latter source(s). Such an apparatus having means for sequentiallystimulating multiple esr transitions, is new and constitutes a furtherfeature of the invention.

Thus viewed from a further aspect the invention provides a temperaturedetermining apparatus, preferably a magnetic resonance imagingapparatus, comprising a first radiation source capable of emitting pulsesequences of a first radiation of a frequency selected to excite nuclearspin transitions in a body, means for detecting free induction decaysignals from said selected nuclei, a second, third and optionally andpreferably at least a fourth radiation source arranged respectively toemit during selected said pulse sequences second, third and optionallyand preferably fourth radiations of selected frequencies capable ofexciting in a paramagnetic substance present in said body one oroptionally and preferably at least two electron spin transitions coupledto the nuclear spin transitions of at least some of said nuclei (saidsecond, third and where present fourth and further radiation sourcespreferably being provided with control means arranged to permitselection of the timing, power and frequency of the second and higherradiations), and generating means arranged to generate a signalindicative of the temperature at one or more sites of said body(preferably an image indicative of the temperature distribution in saidbody) from the free induction decay signals detected by said means fordetecting during pulse sequences in which said body is exposed to saidsecond or third or where appropriate said fourth and higher radiations.

The apparatus of the invention can if desired be provided with a primarymagnet means capable of generating a uniform magnetic field, e.g. ofconventional or lower than conventional field strength, for example 0.01to 2T. However magnet construction and operation are a major factor inthe high cost of conventional MRI apparatus and since the contrasteffect achievable with ESREMRI is so high the apparatus of the inventionmay if desired be provided with a very low field strength primarymagnet, e.g. a magnet capable of generating a field of from 0 to 0.01 T,e.g. about 15 G (1.5 mT), or even with no magnet whatsoever. In thelatter case, the uniform magnetic field in the MRI procedure is providedby the earth's ambient field. There will however normally be means forgenerating the magnetic field gradients which enable the FID signalsfrom particular sites in the body, preferably the complete array ofvoxels forming a complete image of the body, to be distinguished.ESREMRI apparatus without primary magnets, and contrast agents for usetherewith, are disclosed in our copending British Patent Application No.8819753.8.

Operating at the primary magnetic fields of conventional MRI, theradiation required to stimulate nuclear spin transitions, the firstradiation, is generally radiofrequency (RF) radiation, and the radiationrequired to stimulate esr transitions, the second and higher radiations,is generally microwave (MW) radiation. At lower fields or at ambientfield radiations of lower frequencies are required but for the sake ofeasy comprehension the first radiation and the first radiation sourcewill be referred to hereinafter as "RF" radiation and an "RF" source andthe second and higher radiations and the second and higher radiationsources will be referred to as "MW" radiations and "MW" sources It mustbe borne in mind however that, especially where very low field primarymagnets or no primary magnets are used, the "MW" and "RF" radiations maybe at frequencies not normally considered to be MW or RF.

The first radiation source is preferably provided with means foradjusting the pulse timing and duration so that the desired imagingtechnique (e.g. SR, IR, SE, FI, etc.) may be chosen and so that thepulse sequence repetition rate 1/TR may be selected to increase orreduce image acquisition time or to determine T₁, T₂ or nuclear (usuallyproton) density.

The first radiation source is also preferably provided with means foradjusting the central frequency, bandwidth, and intensity of the firstradiation pulses.

In MRI, the radiation pulse which excites the resonating nuclei isapplied while the sample is in a magnetic field conventionally with afield gradient in one direction (e.g. the Z direction). The centralfrequency and bandwidth of the nuclei exciting pulse, together with theZ direction field gradient during the exciting pulse, serve to definethe position along the Z axis and the thickness in the Z direction ofthe slice perpendicular to the Z axis containing nuclei whose spintransitions are excited by that pulse. Thus, for example, Fouriertransformation of a square wave pulse of central frequency V₀ would showsuch a pulse to contain a range of frequencies centered about V₀ andeach corresponding to the Larmor frequency of resonating nuclei in aparticular XY plane along the Z axis. Thus by providing the apparatuswith means for adjusting or selecting the central frequency andbandwidth of the first radiation, the section through the body (theimage zone), and of course the isotopic nature and chemical environmentof the resonating nuclei, may be selected.

The second and higher radiation sources may be one or several emitterswhich may be continuous wave (CW) transmitters or may be arranged toemit pulses or trains of pulses of the second and higher radiations.

To achieve the full benefit of the amplified FID signal of the nuclearspin system and to minimise the required dosage of the paramagneticsubstance, it is therefore beneficial to use second and higher radiationsources capable of emitting a band of frequencies (e.g. in pulse trains)or to use as the sources of each of the second and higher radiations twoor more sources emitting at different frequencies. Insofar as the thirdradiation is concerned it is clearly desirable to excite the second esrtransition as far as is practicable; for the second, fourth and higherradiations however the method of the invention requires that the degreeof saturation of the first esr transition should vary with temperatureand the bandwidths or sets of frequencies of the second, fourth andhigher radiations should be selected accordingly.

To achieve the desired frequency spread in the second and higherradiations, it may be desirable to use pulses of relatively shortduration (hereinafter "micropulses"), for example of the order of nanoor microseconds, and to optimize the amplified population difference ofthe nuclear spin system it may thus be desirable to arrange the secondand higher radiations source to emit a train of micropulses, theadjacent micropulses being so spaced as not to permit seriouslongitudinal relaxation of the electron spin system in the periodsbetween the micropulses.

The apparatus may also if desired be provided with a decoupling meanscomprising a further radiation source arranged to emit radiation capableof exciting spin transitions in certain nuclei (other than theresonating nuclei, that is those nuclei that are responsible for the MRsignals from which the temperature indicative signal or image isgenerated) in order to reduce the number of peaks or peak widths in theesr spectrum of the paramagnetic substance. Where such decoupling meansare provided they should be used only if the resulting partiallydecoupled esr spectrum still contains the temperature independent andtemperature dependent second and first transitions required forperformance of the method of the invention. The further radiationemission may be continuous or pulsed (or may take form of a continuoustrain or a series of trains of micropulses as described earlier for thesecond radiation) and suitably is emitted over substantially the sameperiods as the second and higher radiations.

The second and higher radiation source(s) and, where present, thefurther radiation source will therefore, like the first radiationsource, preferably be provided with means for adjusting pulse timing,pulse duration, central frequency, bandwidth and intensity if they arepulsed sources, and central frequency, bandwidth and intensity if theyare CW emitters.

In the method of the invention the sample is preferably exposed to oneof the second and higher radiations for at least part of each pulsesequence, i.e. during at least part of the period between the initialpulses of adjacent said sequences. Preferably exposure to the second andhigher radiations will be for some, the major part or all of the periodduring which no magnetic field gradient is imposed on the sample.Conveniently therefore one of the second and higher radiations may beapplied following FID signal determination in each pulse sequence, i.e.in the decay period.

It will be appreciated that for certain imaging techniques, particularlysaturation recovery (SR) each "pulse sequence" may only involve onepulse of the first radiation while in other MR imaging techniques eachpulse sequence may involve several pulses of the first radiation.

A magnetic resonance image of the sample can be generated from thedetected FID signals in the conventional manner and the generation ofthe temperature indicative signal or image can be effected for exampleby manipulation of the raw FID signals or by manipulation of theprocessed signals, e.g. data corresponding to the MR images for thefirst, second and higher pluralities of pulse sequences. Thus generallythe apparatus of the invention will comprise means, generally acomputer, for generating the temperature indicative signals or imagesand generally also for transforming sets of detected FID signals, beforeor after manipulation to extract temperature information, into images.

The apparatus of the invention should particularly preferably bearranged to operate as a conventional ESREMRI or MRI apparatus and sothe control means should be arranged to permit the apparatus if desiredto be operated with only the first and second radiations or only thefirst radiation respectively. Similarly if the apparatus is operablewithout a primary magnet it may nonetheless be preferable to provide theapparatus with a primary magnet energisable on operation of selectionmeans so that the apparatus can function for thermographic imaging, forESREMRI or for conventional MRI at higher fields. The apparatus ispreferably arranged to permit MRI or ESREMRI of the body and in certaininstances may simply constitute a conventional MRI or ESREMRI apparatusprovided with the extra radiation sources and data handling meansmentioned above. The image generation procedure involved in the use ofthe apparatus and the method of the invention may also involve any oneof the conventional image generation procedures, such as for exampleback projection or three- or two-dimensional Fourier transformation(3DFT and 2DFT), although the latter two of these may generally bepreferred.

In 2DFT, the sample is placed in a magnetic field (the field directionbeing the Z direction) and is allowed to equilibrate. A small fieldgradient (the slice selection gradient) is then applied, e.g. in the Zdirection, and while the slice selection gradient is superimposed on themain field the sample is exposed to an RF pulse (the initiating pulse)of a given central frequency, bandwidth and duration. Together, thecentral frequency, the bandwidth and the combination of the main fieldand the slice selection gradient serve to define the position andthickness of the image zone, the tomographic section through the sampletransverse to the slice selection gradient in which the resonatingnuclei will be excited by the RF pulse. The duration of the pulsedetermines the resultant change in transverse and longitudinalmagnetization of the resonating nuclei. With a 90° pulse, after theslice selection gradient and the RF pulse are simultaneously terminated,a small field gradient (the phase encoding gradient) is then imposed fora short period in a direction transverse to the slice selectiongradient, e.g. in the Y direction, causing the phase of the oscillatingFID signal to become dependant on the position in the Y direction of thesignal's source and thus encoding spatial information in the phase ofthe FID signal. After the phase encoding gradient is terminated, a thirdsmall field gradient the read gradient) in a direction perpendicular tothe previous two (the X direction) is imposed to encode spatialinformation in the FID frequency and the FID signal is detected and itsintensity as a function of time is recorded during the imposition of theread gradient.

The FID signal that is detected is the combination of signals fromresonating nuclei throughout the image zone. If in simple terms it isviewed as the sum of signals from an array of sources extending in theXY plane, the oscillating signal from each source will have an overallintensity dependent on the local density of the resonating nuclei, afrequency dependant on the position of the source in the X direction anda phase dependant on the position of the source in the Y direction.

The read gradient is terminated after the FID signal decays and, after adelay time to permit equilibration, the slice selection gradient isreimposed and the initiating RF pulse of the subsequent pulse sequenceis applied.

Image generation requires detections of the FID signal for a series ofpulse sequences, each with a phase encoding gradient of differentstrength or duration, and two-dimensional Fourier transformation of theresultant data can extract the spatial information to construct a twodimensional image, in the case described an SR image.

Different imaging techniques, such as IR, SE, etc., or different imagegeneration techniques, e.g. simultaneous slice, volume acquisition, backprojection etc., will of course require different pulse and fieldgradient imposition sequences, sequences which are conventional in theart.

The paramagnetic substance possessing the esr transitions which areexcited by the second and higher radiations may be naturally presentwithin the body being thermographically imaged or, more usually, may beintroduced thereinto as a contrast agent. Coupling with the resonatingnuclei may be either scalar coupling with resonating nuclei within thesame molecules as the unpaired electrons or dipolar coupling withresonating nuclei, generally water protons in the body fluids, inmolecules in the environment of the paramagnetic centres.

Electron spin systems do occur naturally in the body, e.g. in substancessynthesized in certain metabolic pathways such as the oxidation chain inthe cell mitochondria, although normally at low concentration.

Insofar as administered contrast agents are concerned however, in oneembodiment of the invention there may be used a contrast medium whichcontains both the resonating nuclei and the substance possessing thedesired electron spin transition, and in a further embodiment thesubstance possessing the desired electron spin transition may itselfalso contain one or more of the resonating nuclei. This is especiallypreferred where the resonating nuclei are rarely abundant in the samplebeing imaged, for example where the resonating nuclei are ¹³ C or ¹⁹ Fnuclei where scalar coupling will be important in the amplified FID.

Alternatively, and generally more preferably, the contrast agent maycontain a paramagnetic centre which undergoes dipolar coupling withresonating nuclei naturally occurring in the sample, e.g. in bodytissue, or more specifically with resonating protons in water moleculesin the sample.

In the method of the invention, selection of the esr system whichcouples with the resonating nuclei is particularly important where themethod is to be performed on a live subject. Where the body is living itis generally preferable that exposure to penetrating or heatingradiation be minimised and thus it is desirable to select a paramagneticsubstance for which the electron relaxation times T_(2e) and T_(1e) arerelatively long under the local concentration and magnetic fieldconditions and also if possible to use a low primary field so that therequired "MW" radiation has minimal heating effect.

The linewidths of esr transitions (i.e. full widths at half maximum inthe absorption spectrum) are dependent on concentration and magneticfield and the paramagnetic contrast agent will preferably have, at theimaging conditions, an esr spectrum wherein the temperature dependentpeak has a width sufficiently large as to permit an esr enhanced FIDsignal to be detected over the full temperature range of interest, e.g.36° to 45° C. for hyperthermia treatment. In general, the esr peakwidths will preferably be from about 50 milliGauss to 2 Gauss (5 μT to0.2 mT), especially preferably 100 to 1500 milliGauss (10 to 150 μT),more particularly 150 to 800 milliGauss (15 to 80 μT) (or the frequencyequivalents). Thus conventional paramagnetic MRI contrast agents such asthe gadolinium compounds (e.g. Gd DTPA) suggested by Schering AG in EP-A71564 would not generally be selected.

The esr spectrum of the paramagnetic substance, as mentioned above, mustcontain a temperature dependent peak and preferably a temperatureindependent peak. If the spectrum contains further peaks it is generallypreferred that the total number be small, e.g. 2-10, especiallypreferably 3-5, and that the separation of the temperature dependenttransition from the temperature independent transition should be aslarge as possible, e.g. greater than 2 Gauss (0.2 mT), preferablygreater than 10 Gauss (1 mT), especially preferably greater than 15Gauss (1.5 mT) (or the frequency equivalent thereof), especially atambient magnetic field or low primary magnetic fields.

Although it is preferred that the temperature dependent and invariantesr peaks of the paramagnetic substance are those of a doublet ortriplet it is generally preferable to reduce hyperfine splitting in theesr spectrum, and thereby keep the number of peaks in the spectrumsmall. Consequently, the paramagnetic substance will preferably be amolecule containing few non-zero spin nuclei or few non-zero spin nucleiin the vicinity of the paramagnetic centre (e.g. the oxygen of anitroxyl NO moiety). Conveniently, the molecule may have the atoms nearto the paramagnetic centre predominantly selected from zero nuclear spinisotopes or from elements for which the natural abundance of non-zerospin nuclear isotopes is low. Such selection may include elements inwhich the natural abundance of spin =1/2, nuclei is low and isotopessuch as ¹² C, ² H, ³² S, ¹⁴ Si and ¹⁶ O may for example be used to buildup the molecular structure adjacent, to the location of the unpairedelectron.

Particularly interesting as paramagnetic substances for use in thepresent invention are the stable free radicals and in particular thenitroxide stable free radicals many of which have been suggested in theliterature for use as spin labels or as paramagnetic contrast agents forconventional MRI. Moreover, several of these compounds are readilyavailable commercially, for example from Aldrich. The nitroxide stablefree radicals are of particular interest as their toxicities andpharmacokinetics have been studied and show the compounds to be suitablefor in vivo MRI. A further particularly interesting group of stable freeradicals are the deuterated nitroxide stable free radicals of whichseveral have also been suggested in the literature for use as spinlabels.

Where the stable free radicals are only partially deuterated, it isespecially preferred that the hydrogens at those sites where ¹ H wouldcause the greatest, or indeed any significant, reduction in the T_(1e)or T_(2e) values for the unpaired electron should be ² H.

Deuterated radicals used according to the invention preferably havedeuterium atoms in place of protons within 3, preferably 4 andespecially preferably 5 or more, bonds of the paramagnetic centre, e.g.the oxygen of an NO moiety. More especially the radicals are preferablyperdeuterated; however where radicals contain labile hydrogens, e.g.acid, amine or alcohol hydrogens, these may preferably be ¹ H andcompounds containing hydrogens distant from the paramagnetic centrewhich are ¹ H may also be used to advantage.

As nitroxide stable free radicals, or deuterated nitroxide stable freeradicals, there may conveniently be used cyclic nitroxides wherein theNO moiety occurs in a 5 to 7-membered saturated or ethylenicallyunsaturated ring with the ring positions adjacent to it being occupiedby doubly saturated carbon atoms and with one of the remaining ringpositions being occupied by a carbon, oxygen or sulphur atom and theremaining ring positions being occupied by carbon atoms. Alternativelythere may be used as the optionally deuterated nitroxide stable freeradicals compounds in which the NO moiety occurs in a chain where theadjacent chain atoms are carbon and are not bound to any protons.

Preferred nitroxides may be represented by the formula (I) ##STR1##wherein R₁ to R₄ may represent deuterium or lower (for example C₁₋₄)alkyl or hydroxyalkyl groups and R₁ may also represent carboxysubstituted C₁₋₁₀ alkyl groups and R₂ may also represent a higher (e.g.C₅₋₂₀) alkyl group or a carboxy substituted C₁₋₂₀ alkyl group, or R₁ andR₃ may together represent an alkylene or alkenylene group, e.g. havingup to 4, especially preferably up to 3, carbon atoms and X represents anoptionally substituted, saturated or ethylenically unsaturated bridginggroup having 2 to 4 atoms in the backbone of the bridge one of thebackbone atoms being carbon, oxygen or sulphur and the remainingbackbone atoms being carbon, preferably with one or more of R₁ to R₄ andX comprising at least one deuterium, especially preferably anycarbon-bound hydrogen within three, and especially preferably within 4,bonds of the nitroxyl nitrogen being a deuterium atom.

In formula I, the molecule is preferably assymetric and the moieties CR₁R₂ and CR₃ R₄ are preferably different but R₁ to R₄ are nonethelesspreferably deuterium atoms or deuterated alkyl groups.

In formula I the optional substitution on X, which preferably is anoptionally mono-unsaturated C₂₋₃ chain, may for example take the form ofhalogen atoms or oxo, amino, carboxyl, hydroxy or alkyl groups orcombinations or derivatives thereof such as for example amide, ester,ether or N-attached heterocyclic, e.g. 2,5-dioxo-pyrrolidino, groups.Many examples of substituted X groups are described in the literaturementioned in our copending applications.

The nitroxide molecule may if desired be bound to a further substance,such as for example a sugar, polysaccharide, protein or lipid or toother biomolecules, for example to enhance the blood pooling effect orthe tissue- or organ-targetting ability of the nitroxide stable freeradical.

In the method and use of the invention there may particularlyconveniently be used nitroxide stable free radicals selected from thosedescribed in our copending patent applications mentioned above.

A further selection criteria for the paramagnetic substance use in themethod of the invention is that, where the body on which the method isperformed is cellular, e.g. a human or non-human animal, the substanceshould preferably distribute predominantly in the extracellular space.

In a still further aspect the invention thus provides the use of aphysiologically tolerable paramagnetic material having a temperaturedependent and preferably also a temperature independent transition inits esr spectrum, e.g. a stable free radical, for the manufacture of acontrast medium for use in the method of the invention.

It will be appreciated that where references are made herein to thelimits for esr linewidths these will be the linewidths at imagingconditions, e.g. at the imaged sites. Particularly preferably howeverthe linewidth criteria will be satisfied at the local concentrationlimits mentioned below.

The contrast medium may contain, besides the paramagnetic material,formulation aids such as are conventional for therapeutic and diagnosticcompositions in human or veterinary medicine. Thus the media may forexample include solubilizing agents, emulsifiers, viscosity enhancers,buffers, etc. The media may be in forms suitable for parenteral (e.g.intravenous) or enteral (e.g. oral) application, for example forapplication directly into body cavities having external escape ducts(such as the digestive tract,, the bladder and the uterus), or forinjection or infusion into the cardiovascular system. However,solutions, suspensions and dispersions in physiologically tolerablemedia will generally be preferred. Thus in another aspect the inventionalso provides a contrast medium for thermographic imaging comprising aphysiologically tolerable structurally asymmetric nitroxide stable freeradical having a temperature dependent and optionally also a temperatureindependant transition in its esr spectrum, in solution, suspension ordispersion in a physiologically acceptable medium.

For use in in vivo diagnostic imaging, the contrast medium, whichpreferably will be substantially isotonic, may conveniently beadministered at a concentration sufficient to yield a 1 micromolar to 10mM concentration of the paramagnetic substance at the image zone;however the precise concentration and dosage will of course depend upona range of factors such as toxicity, the organ targetting ability of thecontrast agent, and administration route. The optimum concentration forthe paramagnetic substance represents a balance between various factors.In general concentrations may lie in the range 0.1 to 100 mM, especially1 to 10 mM, more especially 2 to 5 mM. Compositions for intravenousadministration preferably will contain the paramagnetic material atconcentrations of 10 to 1000 mM, especially preferably 50 to 500 mM. Forionic materials the concentration will particularly preferably be in therange 50-200 mM, especially 140 to 160 mM and for non-ionic materials200-400 mM, especially 290-330 mM. For imaging of the urinary tract orthe renal system however compositions may perhaps be used havingconcentrations of for example 10-100 mM for ionic or 20 to 200 mM fornon-ionic materials. Moreover for bolus injection, the concentration mayconveniently be 0.1 to 100 mM, preferably 5 to 25 mM, and especiallypreferably 6-15 mM.

The nitroxides in contrast media of the invention will preferablyexhibit esr linewidths of less than 1 Gauss (0.1 millitesla), especiallypreferably less than 100 mG (10 μT), at concentrations of up to 10 mM,especially at 1 or 2 mM.

As discussed above, non-invasive thermographic imaging is particularlydesirable for treatment of malignant tissue by hyperthermia, although itis also of general use in the detection and location of abnormaltissues, and in one particularly preferred embodiment the apparatus ofthe invention is further provided with sources of directable tissuedestroying radiation, e.g. microwave emitters, which may be operated totreat body sites identified as being malignancy locations.

In a further preferred embodiment, the MW emitter used to generate theesr excitation described above can also serve as the radiation sourcefor hyperthermic treatment.

Such sources of directable radiation are preferably provided withmovable mounting means so as to be locatable to emit tissue destroyingradiation in a selected direction.

In this way the heating effect of the tissue destroying radiation may bemonitored by the apparatus of the invention enabling the tissuedestroying radiation sources to be so located as to avoid generation ofhot spots in healthy tissue and to avoid irradiating tissues which mightshadow the malignancy locations and so prevent the temperature increaseat such locations from being sufficient. Alternatively, the radiationsources may of course be held static if the apparatus is provided withmeans for adjusting the position of the body being imaged.

Thus viewed from a yet further aspect the invention provides a processof treating malignant tissue in a body by irradiation with tissuedestroying radiation, which method comprises thermographically imagingsaid body or said malignant tissue therein by the method of theinvention and adjusting the direction and/or duration of irradiation ofsaid body by tissue destroying radiation to reduce thermal damage tohealthy tissue within said body.

BRIEF DESCRIPTION OF THE INVENTION

The invention will now be described further by way of example and withreference to the accompanying drawings in which:

FIG. 1 is a schematic perspective drawing of a thermographic imagingapparatus according to the invention; and

FIG. 2 is a schematic perspective view of the emitters of the first tothird radiation in the apparatus of FIG. 1.

Referring to FIG. 1, there is shown an ESREMRI apparatus 1 having asample 2, dosed with a paramagnetic contrast medium manufacturedaccording to the invention, placed at the axis of the coils ofelectromagnet 3. Power from DC supply 4 to the electromagnet 3 enables aprimary magnetic field to be generated if the apparatus is to be used inconventional MRI or ESREMRI. For the new method the inventionelectromagnet 3 is energised if imaging is to be effected in a generatedprimary magnetic field.

The apparatus is further provided with resonators 5, 6 and 19 foremitting the first, second and third radiations respectively. Resonator5 is connected to "RF" transceiver 7 powered by power supply 8 andresonator 6 and 19 are connected, for example by waveguides, to "MW"generators 9 and 21 which are powered by power supplies 10 and 20.

"MW" generators 9 and 21 may be arranged to emit "MW" radiation havingmore than one maximum frequency in order to excite more than one esrtransition.

In one particularly preferred embodiment the apparatus of the inventionis further provided with source (22) of directable tissue destroyingradiation, e.g. microwave emitters, which may be operated to treat bodysites identified as being malignancy locations. In a further preferredembodiment, the MW EMITTER used to generate the esr excitation describedabove can also serve as the radiation source for hyperthermic treatment.

The frequency selection, bandwidth, pulse duration and pulse timing ofthe first, second and third radiations emitted by resonators 5, 6 and 19are controlled by control computer 11 and interface module 18 which alsocontrol the energisation or deenergisation of electromagnet 3.

Computer 11 also controls the power supply from power sources 12, 13 and14 to the three pairs of Helmholtz coils 15, 16 and 17 which are shownin further detail in FIG. 2. The coils of coil pair 15 are coaxial withthe coils of electromagnet 3 and the saddle coils of coil pairs 16 and17 are arranged symmetrically about that axis, the Z axis, with theirown axes mutually perpendicular and perpendicular to the Z axis. Coilpairs 15, 16 and 17 are used to generate the magnetic field gradientsthat are superimposed on the uniform field at various stages of theimaging procedure, e.g. in two-dimensional Fourier transform imaging,and the timing sequence for operation of the coil pairs and foroperation of the "MW" generator and the "RF" transceiver is controlledby computer 11 and interface module 18.

The apparatus may also be provided with decoupler comprising a further"RF" resonator connected to an "RF" transmitter and a power supply (notshown) and controlled by computer 11. The decoupler may be operated toemit a further radiation at a frequency selected to excite the nuclearspin transition in non-zero spin nuclei in the contrast agent.

In operation the power supply to electromagnet 3 may be switched on oroff depending on whether the apparatus is to be operated at ambient orhigher magnetic fields. The sample 2, e.g. a patient, is placed withinthe coil cavity and the imaging procedure is begun.

Interface module 18 activates the power supply to coil pair 15 for ashort time period during which DC current flowing through the coils ofcoil pair 15 in opposite directions about the Z axis results in anapproximately linear field gradient in the Z direction being imposed onthe ambient field.

Within the time period for which coil pair 15 is energized, interfacemodule 18 activates "RF" transceiver 7 to cause resonator 5 to emit an"RF" pulse, e.g. a 90° pulse, to excite the nmr transition of thoseresonating nuclei (generally protons) whose Larmor frequenciescorrespond to the frequency band of the "RF" pulse. The duration,intensity, band width and central frequency of the "RF" pulse may beselected by computer 11.

Effectively the "RF" pulse serves to excite the MR transition of theselected non-zero nuclear spin isotope (generally water protons) withina cross-section (the image zone) of the sample that is transverse to buthas thickness in the Z direction.

On termination of the "RF" pulse, current in coil pair 15 is alsoterminated and after a very short delay interface module 18 energizescoil pair 16 to provide a field gradient in the Y direction for a shorttime period. This is termed the phase encoding gradient as the fieldgradient causes the Larmor frequency for the resonating nuclei to varylinearly across the image zone in the Y direction for the period thatcoil pair 15 is energized. With the removal of the perturbation of theLarmor frequencies on termination of the phase encoding gradient, theoscillation frequencies of the contributions to the FID signal fromdifferent source areas of the image zone return to being substantiallythe same, but the phases of such contributions are shifted to an extentdependant on the location of the particular source area along the Ydirection.

After terminating current in coil pair 16, the interface module 18 thenenergizes coil pair 17 to provide a field gradient (the read gradient)in the X direction, and reactivates "RF" transceiver 7 to detect the FIDsignal from the sample.

The FID signal is assumed to arise from the transverse magnetization ofthe nuclear spin system within the image zone since the MR transitionwas excited by the "RF" pulse for resonating nuclei in this zone only.As described above, the intensity of the FID signal as a function oftime contains encoded information regarding the distribution of theresonating nuclei in the image zone in the X and Y directionsrespectively .

The FID signal intensity falls off exponentially with time as the systemdephases and the period for which the read gradient is imposed and thetransceiver 7 detects the FID signal from the sample is generally veryshort, for example of the order of milliseconds.

To generate an MR image of the image zone it is necessary to repeat thepulse and detection sequence for many further times, e.g. 64-1024 times,each time generating phase encoding gradients of different magnitude orduration. Often, to produce a good S/N ratio, signals for several, e.g.2-4, identically performed sequences will be summed. FID signals foreach set of sequences are transformed by the computer 11 using astandard two-dimensional Fourier transform algorithm to produce thedesired spatial images of the image zone.

In conventional MRI, after termination of the only or the last FIDsignal detection period in a pulse and detection sequence and before thesubsequent imposition of the slice selection gradient and emission ofthe initiating RF pulse of the next sequence, it has been necessary towait for a delay period, generally of the order of seconds, until theresonating nuclei have relaxed to near equilibrium in order to build upsufficient longitudinal magnetization for the FID signal following thenew RF pulse to be sufficiently strong to give an acceptable S/N ratio.

However, in ESREMRI, the delay period following the only or the lastdetection period may be reduced by the use of the amplified nuclearpopulation difference resulting from the coupling between the electronMR and nuclear MR transitions. Alternatively put, by irradiating thesample with "MW" radiation before the or each "RF" pulse, amplificationof the nuclear spin state population difference relative to thepopulation difference at equilbrium in the absence of "MW" irradiationmay be achieved thus enabling the FID signal to be enhanced. Thus forexample in at least the period between termination of the last readgradient for each pulse sequence and the emission of the initiating "RF"pulse of the next sequence, for example for a period of about 10 ms to100 ms, interface module 18 activates "MW" generator 9 or 21 to causethe sample to be irradiated with "MW" radiation of a selected power andof a central frequency corresponding to the Larmor frequency of atemperature independent or a temperature dependent esr transition of theparamagnetic centre in the contrast agent in the sample; either CWradiation or, preferably, a train of radiation pulses.

The selection of the "MW" frequency and power is made by computer 11which also transforms the detected FID signals in the manner describedto yield an MRI image indicative of the thermal distribution across theimage zone.

To minimise field inhomogeneities, the sample cavity of the apparatus ofthe invention should preferably be provided with shielding (not shown),conveniently shielding which may be moved into place between theelectromagnet 3 and the Helmholtz coils 15, 16 and 17 and/or permanentshielding between coils 15, 16 and 17 and the electronic controlequipment and power sources (4, 7-14, 18).

I claim:
 1. A method of determining temperature of at least one site ofa body containing a paramagnetic substance having a first electron spinresonance transition, the central frequency of which is temperaturedependent, said method comprising exposing said body to a firstradiation of a frequency selected to excite nuclear spin transitions inselected nuclei in said body, exposing said body to a second radiationof a frequency selected to excite said electron spin resonancetransition, said second radiation being at the central frequency of saidelectron spin resonance transition at a selected reference temperature,detecting free induction decay signals from the body, and from said freeinduction decay signals generating a signal indicative of thetemperature at said site.
 2. A method as claimed in claim 1 wherein saidparamagnetic substance has a second electron spin resonance transition,the central frequency of which is temperature independent, said methodfurther comprising exposing said body to a third radiation of afrequency selected to excite said second electron spin resonancetransition.
 3. A method as claimed in claim 2 wherein said body isexposed to a series of pulse sequences of said first radiation and isexposed to said second radiation during a first set of said sequencesand to said third radiation during a second set of said sequences, saidmethod comprising generating said signal indicative of temperature fromthe free induction decay signal detected in said first and secondsequences.
 4. A method as claimed in claim 1 wherein exposure of saidbody to said second and third radiations is effected at at least twodifferent power levels.
 5. A method as claimed in claim 2 comprising thefollowing steps:a) distributing the paramagnetic substance within saidbody; b) exposing said body to a series of pulse sequences of said firstradiation; c) exposing said body during a first set of said sequences tosaid second radiation at a first selected power level; d) detecting freeinduction decay signals from said body in said first set of sequences;e) exposing said body during a second set of said sequences to a thirdradiation of a frequency selected to excite said second electron spinresonance transition at said first selected power level; f) detectingfree induction decay signals from said body in said second set ofsequences; g) exposing said body during a third set of said sequences tosaid second radiation at a second selected power level; h) detectingfree induction decay signals from said body in said third set ofsequences; i) exposing said body during a fourth set of said sequencesto said third radiation at said second selected power level; j)detecting free induction decays signals from said body in said fourthset of sequences; k) exposing said body during a fifth set of saidsequences to a fourth radiation of a frequency selected to excite saidfirst electron spin resonance transition, said fourth radiation being atthe central frequency of said first electron spin resonance transitionat a second selected reference temperature and said fourth radiationbeing at said first selected power level; l) detecting free inductiondecay signals from said body in said fifth set of sequences; and m)generating from the free induction signals detected in steps (d), (f),(h), (j) and (l) the signal indicative of temperature.
 6. A method asclaimed in claim 2 comprising the following steps:a) distributing theparamagnetic substance within said body; b) exposing said body to aseries of pulse sequences of said first radiation; c) exposing said bodyduring a first set of said sequences to said second radiation at a firstselected power level; d) detecting free induction decay signals fromsaid body in said first set of sequences; e) exposing said body during asecond set of said sequences to a third radiation of a frequencyselected to excite said second electron spin resonance transition atsaid first selected power level; f) detecting free induction decaysignals from said body in said second set of sequences; g) exposing saidbody during a third set of said sequences to said second radiation at asecond selected power level; h) detecting free induction decay signalsfrom said body in said third set of sequences; i) exposing said bodyduring a fourth set of said sequences to said third radiation at saidsecond selected power level; j) detecting free induction decays signalsfrom said body in said fourth set of sequences; k) exposing said bodyduring a fifth set of said sequences to a fourth radiation of afrequency selected to excite said first electron spin resonancetransition, said fourth radiation being at the central frequency of saidfirst electron spin resonance transition at a second selected referencetemperature and said fourth radiation being at said first selected powerlevel; l) detecting free induction decay signals from said body in saidfifth set of sequences; and m) generating from the free inductionsignals detected in steps (d), (f), (h), (j) and (l) the signalindicative of temperature.
 7. A method as claimed in claim 1 furthercomprising exposing said body to a further radiation of a frequencyselected to excite said first electron spin resonance transition, saidfurther radiation being at the central frequency of said first electronspin resonance transition at a second selected reference temperature. 8.A method as claimed in claim 1 wherein said body is a human or animalbody and said paramagnetic substance is a physiologically tolerablematerial administered to said body.
 9. A method as claimed in claim 1which further comprises generating free induction decay signalsindicative of the temperature at a plurality of sites in said body, andgenerating therefrom an image of temperature distribution in said body.10. A temperature determining apparatus comprising a first radiationsource means which emits pulse sequences of a first radiation of afrequency selected to excite nuclear spin transitions in a body, meansfor detecting free induction decay signals from said selected nuclei, asecond and third radiation source means which respectively emit duringselected said pulse sequences second and third radiations of frequenciesselected to excite in a paramagnetic substance present in said body oneor more electron spin transitions coupled to the nuclear spintransitions of at least some of said nuclei, and generating meansarranged to generate a signal indicative of the temperature at one ormore sites of said body from the free induction decay signals detectedby said means for detecting during pulse sequences in which said body isexposed to said radiations.
 11. An apparatus as claimed in claim 10further comprising a fourth radiation source means which emits a fourthradiation of a frequency selected to excite in a paramagnetic substancepresent in said body an electron spin transition coupled to the nuclearspin transition of at least some of said nuclei.
 12. An apparatus asclaimed in claim 11 further comprising a fifth radiation source meanswhich emits during selected said pulse sequences a fifth radiation, saidsecond, third, fourth and fifth radiations being of selected frequenciesto excite in a paramagnetic substance present in said body at least twoelectron spin transitions coupled to the nuclear spin transitions of atleast some of said nuclei.
 13. An apparatus as claimed in claim 12wherein said second, third, fourth and fifth radiation source means areprovided with control means which permit selection of the timing, powerand frequency of said second and higher radiations.
 14. An apparatus asclaimed in claim 10 further comprising means for providing magneticresonance image of said body.
 15. An apparatus as claimed in claim 10further provided with means for generating a source of directable tissuedestroying radiation responsive to the signal indicative of thetemperature at one or more sites of said body.
 16. A process fortreating malignant tissue in a body by irradiation with tissuedestroying radiation, which process comprises thermographically imagingsaid body or said malignant tissue therein by a method which comprisesadministering to said body a paramagnetic substance having a firstelectron spin resonance transition, the central frequency of which istemperature dependent, exposing said body to a first radiation of afrequency selected to excite nuclear spin transitions in selected nucleiin said body, exposing said body to a second radiation of a frequencyselected to excite said electron spin resonance transition, said secondradiation being at the central frequency of said electron spin resonancetransition at a selected reference temperature, detecting free inductionsignals from said body, generating from said free induction decaysignals an image indicative of the temperature in said body, andadjusting the direction of irradiation of said body by said tissuedestroying radiation to reduce thermal damage to healthy tissue withinsaid body.
 17. A process of treating malignant tissue in a body byirradiation with tissue destroying radiation, which process comprisesthermographically imaging said body or said malignant tissue therein bya method which comprises administering to said body a paramagneticsubstance having a first electron spin resonant transition, the centralfrequency of which is temperature dependent, exposing said body to afirst radiation of a frequency selected to excite nuclear spintransitions in selected nuclei in said body, exposing said body to asecond radiation of a frequency selected to excite said electron spinresonance transition, said second radiation being at the centralfrequency of said electron spin resonance transition at a selectedreference temperature, detecting free induction signals from said body,generating from said free induction decay signals an image indicative ofthe temperature in said body, said adjusting the duration of irradiationof said body by said tissue destroying radiation to reduce thermaldamage to healthy tissue within said body.
 18. A process of treatingmalignant tissue in a body by irradiation with tissue destroyingradiation, which process comprises thermographically imaging said bodyor said malignant tissue therein by adjusting the direction and durationwhich comprises administering to said body a paramagnetic substancehaving a first electron spin resonant transition, the central frequencyof which is temperature dependent, exposing said body to a firstradiation of a frequency selected to excite nuclear spin transitions inselected nuclei in said body, exposing said body to a second radiationof a frequency selected to excite said electron spin resonancetransition, said second radiation being at the central frequency of saidelectron spin resonance transition at a selected reference temperature,detecting free induction signals from said body, generating from saidfree induction decay signals an image indicative of the temperature insaid body, and adjusting the direction and duration of irradiation ofsaid body by said tissue destroying radiation to reduce thermal damageto healthy tissue within said body.